Published ahead of print on May 31, 2007, doi:10.1165/rcmb.2006-0176OC Am. J. Respir. Cell Mol. Biol., Volume 37, Number 3, September 2007, 347-356 A more recent version of this article appeared on September 1, 2007
Submitted on May 17, 2006 Restoration of W1282X CFTR Activity by Enhanced ExpressionSteven M Rowe1*,1 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA, 2 the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA, 3 the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA, 4 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA; the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA, 5 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA * To whom correspondence should be addressed. E-mail: smrowe{at}uab.edu.
Cystic Fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Premature termination codons represent a common minority of CFTR mutations, and are caused by base pair substitutions that produce abnormal stop codons in the coding sequence. Select aminoglycosides induce 'translational readthrough' of premature stop codons and have been shown to restore full-length functional protein in a number of preclinical and clinical settings. We studied two well described premature termination codons found in the distal open reading frame of CFTR, W1282X and R1162X, expressed in polarizing and non-polarizing cells. Our findings indicate that W1282X CFTR expressing cells demonstrate significantly greater CFTR activity when over expressed compared to R1162X CFTR cells, even when truncated protein is the predominant form. In addition, our results show the combination of stimulated expression and stop codon suppression produces additive effects on CFTR mediated ion transport. These findings provide evidence that W1282X CFTR exhibits membrane localization and retained chloride channel function following enhanced expression, and suggest that patients harboring this mutation may be more susceptible to CFTR rescue.
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